Tisagenlecleucel Versus Standard of Care in Adult Patients With Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma: A Randomized, Open Label, Phase III Trial (BELINDA)

ClinicalTrials.gov Identifier: NCT03570892 | Novartis reference number: CCTL019H2301 | Last updated on: July 14, 2020

 

All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation.

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Trial purpose

This is a randomized, open label, multicenter phase III trial comparing the efficacy, safety, and tolerability of tisagenlecleucel to Standard Of Care in adult patients with aggressive B-cell Non-Hodgkin Lymphoma after failure of rituximab and anthracycline containing frontline immunochemotherapy.

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Trial summary

condition

CONDITION

Non-Hodgkin Lymphoma

Phase

PHASE

Phase 3

study type

STUDY TYPE

Interventional  (Clinical Trial)

Gender

GENDER(S)

All

Age

AGE(S)

18 Years and older   (Adult, Older Adult)

Accepts healthy volunteers

ACCEPTS HEALTHY VOLUNTEERS

No

Estimated completion date

ACTUAL START DATE

May 7, 2019

Estimated completion date

ESTIMATED COMPLETION DATE

March 31, 2026

estimated enrolment

ESTIMATED ENROLLMENT

318 participants

Recruitment status

RECRUITMENT STATUS

Recruiting

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Eligibility criteria

Inclusion Criteria:

  1. Histologically confirmed, aggressive B-cell NHL at relapse/progression or PR after front line therapy. Aggressive B-cell NHL is heretofore defined by the following list of subtypes (Swerdlow et al 2016):

    1. DLBCL, NOS,
    2. FL grade 3B,
    3. Primary mediastinal large B cell lymphoma (PMBCL),
    4. T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL),
    5. DLBCL associated with chronic inflammation,
    6. Intravascular large B-cell lymphoma,
    7. ALK+ large B-cell lymphoma,
    8. B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and classical Hodgkin's Lymphoma (HL)),
    9. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,
    10. High-grade B-cell lymphoma, NOS
    11. HHV8+ DLBCL, NOS
    12. DLBCL transforming from follicular lymphoma
    13. DLBCL transforming from marginal zone lymphoma
    14. DLBCL, leg type
  2. Relapse or progression within 365 days from last dose of anti CD20 antibody and anthracycline containing first line immunochemotherapy or refractory (have not achieved a CR).
  3. Patient is considered eligible for autologous HSCT as per local investigator assessment. Note: Intention to transplant and type of high dose chemotherapy (HDCT) regimen will be documented at the time of study entry
  4. Disease that is both active on PET scan (defined as 5-Deauville scorepoint-scale of 4 or 5) and measurable on CT scan, defined as::

    1. Nodal lesions >15 mm in the long axis, regardless of the length of the short axis, and/or
    2. Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) >10 mm in long AND short axis
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  6. Adequate organ function:

    Renal function defined as:

    1. Serum creatinine of ≤1.5 x upper limit of normal (ULN), OR estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2

      Hepatic function defined as:

    2. Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN
    3. Total bilirubin ≤ 1.5 x ULN with the exception of patients with Gilbert syndrome who may be included if their total bilirubin is ≤3.0 × ULN and direct bilirubin ≤1.5 × ULN

      Hematologic Function (regardless of transfusions) defined as:

    4. Absolute neutrophil count (ANC) >1000/mm3
    5. Absolute lymphocyte count (ALC) >300/mm3 OR Absolute number of CD3+ T cells >150/mm3 (only for patients with non-historical apheresis)
    6. Platelets ≥50000/mm3
    7. Hemoglobin >8.0 g/dl

      Adequate pulmonary function defined as:

    8. No or mild dyspnea (≤ Grade 1)
    9. Oxygen saturation measured by pulse oximetry > 90% on room air
    10. Forced expiratory volume in 1 s (FEV1) ≥ 50% and/or carbon monoxide diffusion test (DLCO) ≥50% of predicted level
  7. Must have a leukapheresis material of non-mobilized cells available for manufacturing.

Exclusion Criteria:

  1. Prior treatment with anti-CD19 therapy, T cell therapy, or any prior gene therapy product
  2. Treatment with any systemic lymphoma-directed second line anticancer therapy prior to randomization. Only steroids and local irradiation are permitted for disease control
  3. Patients with active central nervous system (CNS) involvement by disease under study are excluded, except if the CNS involvement has been effectively treated and local treatment was >4 weeks before randomization
  4. Prior allogeneic HSCT
  5. Clinically significant active infection
  6. Any of the following cardiovascular conditions:

    • Unstable angina, myocardial infarction, coronary artery bypass graft (CABG), or stroke within 6 months prior to screening,
    • Left ventricle ejection fraction (LVEF) <45% as determined by echocardiogram (ECHO) or magnetic resonance angiography (MRA) or multigated acquisition (MUGA) at the screening assessment.
    • New York Heart Association (NYHA) functional class III or IV (Chavey et al 2001), within the past 12 months.
    • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II) and third degree AV block unless adequately controlled by pacemaker implantation.
    • Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or inability to determine the QTcF interval
    • Risk factors for Torsades de Pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia, or any of the following:
    • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome
    • Concomitant medication(s) with a "Known Risk of Torsades de Pointes" per crediblemeds.org that cannot be discontinued or replaced by safe alternative medication.
  7. Patients with active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré Syndrome (GBS), Amyotrophic Lateral Sclerosis (ALS)) and clinically significant active cerebrovascular disorders (e.g. cerebral edema, posterior reversible encephalopathy syndrome (PRES))

 

Other protocol-defined inclusion and exclusion criteria may apply.

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Intervention

Drug: Tisagenlecleucel after optional bridging and lymphodepleting chemotherapy

Drug: Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT)

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Trial locations 

United States, California
Moores UC San Diego Cancer Center    Recruiting
La Jolla, California, United States, 92093
Contact: Viktoriya Duda    858-822-5364    [email protected]   
Principal Investigator: Carolyn Mulroney         
University of California Los Angeles University of California LA    Recruiting
Los Angeles, California, United States, 90095
Contact: Ghadi Ghanem    310-825-7412    [email protected]   
Principal Investigator: Herbert Eradat         
UCSF Medical Center    Recruiting
San Francisco, California, United States, 94143
Contact: Charlie Aoun    415-353-1351    [email protected]   
Principal Investigator: Charalambos Andreadis         

United States, Colorado
Sarah Cannon Research Institute    Recruiting
Denver, Colorado, United States, 80218
Contact: Caleb Cleveland    720-754-4800    [email protected]   
Principal Investigator: Peter McSweeney         

United States, Florida
Mayo Clinic Jacksonville    Recruiting
Jacksonville, Florida, United States, 32224
Contact: Brittany Mason    904-953-6806    [email protected]   
Principal Investigator: Mohamed Kharfan Dabaja         

United States, Georgia
Emory University School of Medicine/Winship Cancer Institute SC    Recruiting
Atlanta, Georgia, United States, 30322
Contact: Deanna Hill       [email protected]   
Principal Investigator: Jonathon Cohen         

United States, Illinois
University of Chicago Medical Center Hematology and Oncology    Recruiting
Chicago, Illinois, United States, 60637
Contact    773-834-8980      
Principal Investigator: Michael R. Bishop         

United States, Kansas
University of Kansas Cancer Center SC    Recruiting
Kansas City, Kansas, United States, 66205
Contact: Dana Wheeler       [email protected]   
Principal Investigator: Joseph P McGuirk         

United States, Michigan
Wayne State University - Karmanos Cancer Institute SC    Recruiting
Detroit, Michigan, United States, 48201
Contact: Suanne Minh Dorr    313-576-9271    [email protected]   
Principal Investigator: Abinav Deol         

United States, Nebraska
University of Nebraska Medical Center    Recruiting
Omaha, Nebraska, United States, 68198
Contact: Maribeth Hohenstein    402-559-6275    [email protected]   
Principal Investigator: Julie M. Vose         

United States, New Jersey
Hackensack University Medical Center    Recruiting
Hackensack, New Jersey, United States, 07601
Contact    201-996-2000      
Principal Investigator: Lori Leslie   

United States, North Carolina
Duke University Medical Center    Recruiting
Durham, North Carolina, United States, 27705
Contact: Bonnie Toaso    919-681-4769    [email protected]   
Principal Investigator: Matthew S. McKinney         

United States, Ohio
Jewish Hospital    Recruiting
Cincinnati, Ohio, United States, 45236
Contact: Alessa Hubbell    513-794-5482    [email protected]   
Principal Investigator: James H Essell         
The Ohio State University SC    Recruiting
Columbus, Ohio, United States, 43210
Contact: Heather Heise    614-366-7421    [email protected]   
Principal Investigator: David A Bond         

United States, Oregon
Oregon Health Sciences Univ SC    Recruiting
Portland, Oregon, United States, 97239
Contact: Jacqueline Brown    503-494-4603    [email protected]   
Principal Investigator: Richard T. Maziarz         

United States, Pennsylvania
University of Pennsylvania, Abramson Cancer Center    Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Brittany Koch    215-662-6394    [email protected]   
Principal Investigator: Stephen Schuster         

United States, South Carolina
MUSC Hollings Cancer Center    Recruiting
Charleston, South Carolina, United States, 29425
Contact: Shanta Salzer       [email protected]   
Principal Investigator: Brian Hess         

United States, Tennessee
Sarah Cannon Research Institute    Recruiting
Nashville, Tennessee, United States, 37203
Contact: Renee Thompson       [email protected]   
Principal Investigator: Ian W. Flinn         

United States, Texas
Baylor Scott and White Research Institute    Recruiting
Dallas, Texas, United States, 75231
Contact: Joyce Ghormley    214-987-6915    [email protected]   
Principal Investigator: Houston Holmes         
University of Texas MD Anderson Cancer Center MD Anderson Cancer Center    Recruiting
Houston, Texas, United States, 77030
Contact: Katherine Annandale    713-792-2860    [email protected]   
Principal Investigator: Jason Westin         
Methodist Hospital    Recruiting
San Antonio, Texas, United States, 78229
Contact: George DeLeon    210-575-3817    [email protected]   
Principal Investigator: Paul Shaughnessy         

United States, Wisconsin
University of Wisconsin Carbone Cancer Center    Recruiting
Madison, Wisconsin, United States, 53792-6164
Contact    608-265-3794      
Principal Investigator: Vaishalee Kenkre         

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